Claims for Patent: 11,723,869

Summary for Patent: 11,723,869

Title:	Freeze-dried product and gas-filled microvesicles suspension
Abstract:	A method of manufacturing a suspension of gas-filled microvesicles by reconstituting a freeze-dried product and a suspension obtained according to said method, where the freeze-dried product has been subjected to a thermal treatment.
Inventor(s):	Philippe Bussat, Anne Lassus, Jean Brochot, Michel Schneider, Feng Yan
Assignee:	Bracco Suisse SA
Application Number:	US17/872,974
Patent Claims:	1. A suspension of gas-filled microvesicles comprising a freeze-dried product dissolved in a pharmaceutically acceptable liquid carrier, said freeze-dried product comprising 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), dipalmitoylphosphatidylglycerol sodium salt (DPPG-Na), palmitic acid and polyethylene glycol 4000 (PEG4000), wherein said suspension has a value of critical pressure (Pc50) of at least 20 kPa, and wherein the microvesicles are filled with a SF6 gas. 2. The suspension according to claim 1, wherein said suspension has a value of Pc50 of at least 22 kPa. 3. The suspension according to claim 1, wherein said suspension has a value of Pc50 of at least 25 kPa. 4. The suspension according to claim 1, wherein said suspension has a value of Pc50 of from 20 kPa to 32 kPa. 5. The suspension according to claim 1, wherein the weight ratio DSPC/DPPG-Na/palmitic acid is of 4.75/4.75/1. 6. The suspension of claim 5, wherein the weight ratio between DSPC/DPPG-Na/palmitic acid and PEG4000 is of 0.017:1. 7. A freeze-dried product obtained according to a method comprising: a. preparing a liquid mixture comprising (i) an amphiphilic material comprising 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), dipalmitoylphosphatidylglycerol (DPPG) and palmitic acid; and (ii) a polyethylene glycol as freeze-drying protecting component in a solvent; b. sampling said liquid mixture into a glass vial; c. freeze-drying the liquid mixture to remove said solvent and obtain a freeze-dried product; and d. after completion of the freeze-drying of step c: saturating a headspace of said vial with a SF6 gas; and heating said freeze-dried product at ambient pressure at a temperature higher than 35° C. and lower than the melting point of the polyethylene glycol freeze-drying protecting component, for a period of time of from eight to twenty hours, wherein the freeze-dried product of step c has not been reconstituted prior to step d, and wherein the freeze-dried product is suitable for the preparation of a suspension of stabilized gas-filled microbubbles. 8. A method of diagnosing which comprises (i) administering to a patient the suspension of gas-filled microvesicles according to claim 1; (ii) applying an ultrasound beam to the patient; and detecting an ultrasound signal from a region of interest in said patient. 9. The method according to claim 8, wherein the region of interest in said patient is the heart. 10. The method according to claim 8, wherein the region of interest in said patient is the liver. 11. The method according to claim 8, wherein the region of interest in said patient is the urinary tract. 12. The method according to claim 8, wherein said suspension has a value of Pc50 of from 20 kPa to 32 kPa. 13. The method according to claim 8, wherein the weight ratio DSPC/DPPG-Na/palmitic acid is of 4.75/4.75/1. 14. The method according to claim 13, wherein the weight ratio between DSPC/DPPG-Na/palmitic acid and PEG4000 is of 0.017:1. 15. The suspension of gas-filled microvesicles according to claim 1 obtained according to a method comprising: a. preparing a liquid mixture comprising (i) an amphiphilic material comprising 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), dipalmitoylphosphatidylglycerol sodium salt (DPPG-Na) and palm itic acid; and (ii) a polyethylene glycol as freeze-drying protecting component in a solvent; b. sampling said liquid mixture into a glass vial; c. freeze-drying the liquid mixture to remove said solvent and obtain a freeze-dried product; d. after completion of the freeze-drying of step c: saturating a headspace of said vial with a SF6 gas; and heating said freeze-dried product at ambient pressure at a temperature higher than 35° C. and lower than the melting point of the polyethylene glycol freeze-drying protecting component, for a period of time of from eight to twenty hours, wherein the freeze-dried product of step c has not been reconstituted prior to step d; and e. reconstituting the freeze-dried product with a pharmaceutically acceptable liquid carrier in the presence of said SF6 gas under gentle agitation to obtain the suspension of gas-filled microvesicles. 16. The freeze-dried product according to claim 7 wherein the glass vial is stoppered and sealed after saturating the headspace of said vial with said SF6 gas. 17. A method of diagnosing which comprises (i) reconstituting the freeze-dried product according to claim 7 with a pharmaceutically acceptable liquid carrier in the presence of said SF6 gas under gentle agitation to obtain a suspension of gas-filled microvesicles; (ii) administering to a patient the suspension of gas-filled microvesicles; (iii) applying an ultrasound beam to the patient and detecting an ultrasound signal from a region of interest in said patient. 18. The method according to claim 17, wherein the region of interest in said patient is the heart. 19. The method according to claim 17, wherein the region of interest in said patient is the liver. 20. The method according to claim 17, wherein the region of interest in said patient is the urinary tract.